The present invention relates generally to oxime ethers which are useful as antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex, to pharmaceutical compositions containing such compounds, processes for preparing such compounds, and to methods of using these compounds for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.
Hemostasis is the normal physiological process in which bleeding from an injured blood vessel is arrested. It is a dynamic and complex process in which platelets play a key role. Within seconds of vessel injury, resting platelets become activated and are bound to the exposed matrix of the injured area by a phenomenon called platelet adhesion. Activated platelets also bind to each other in a process called platelet aggregation to form a platelet plug. The platelet plug can stop bleeding quickly, but it must be reinforced by fibrin for long-term effectiveness, until the vessel injury can be permanently repaired.
Thrombosis may be regarded as the pathological condition wherein improper activity of the hemostatic mechanism results in intravascular thrombus formation. Activation of platelets and the resulting platelet aggregation and platelet factor secretion has been associated with a variety of pathophysiological conditions including cardiovascular and cerebrovascular thromboembolic disorders, for example, the thromboembolic disorders associated with unstable angina, myocardial infarction, transient ischemic attack, stroke, atherosclerosis and diabetes. The contribution of platelets to these disease processes stems from their ability to form aggregates, or platelet thrombi, especially in the arterial wall following injury.
Platelets are activated by a wide variety of agonists resulting in platelet shape change, secretion of granular contents and aggregation. Aggregation of platelets serves to further focus clot formation by concentrating activated clotting factors at the site of injury. Several endogenous agonists including adenosine diphosphate (ADP), serotonin, arachidonic acid, thrombin, and collagen, have been identified. Because of the involvement of several endogenous agonists in activating platelet function and aggregation, an inhibitor which acts against all agonists would represent a more efficacious antiplatelet agent than currently available antiplatelet drugs, which are agonist-specific.
Current antiplatelet drugs are effective against only one type of agonist; these include aspirin, which acts against arachidonic acid; ticlopidine, which acts against ADP; thromboxane A2 synthetase inhibitors or receptor antagonists, which act against thromboxane A2; and hirudin, which acts against thrombin.
Recently, a common pathway for all known agonists has been identified, namely platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa), which is the membrane protein mediating platelet aggregation. A recent review of GPIIb/IIIa is provided by Phillips et al. Cell (1991) 65: 359-362. The development of a GPIIb/IIIa antagonist represents a promising new approach for antiplatelet therapy.
GPIIb/IIIa on unstimulated platelets does not bind soluble proteins, but GPIIb/IIIa on activated platelets is known to bind four soluble adhesive proteins, namely fibrinogen, von Willebrand factor, fibronectin, and vitronectin. The binding of fibrinogen and von Willebrand factor to GPIIb/IIIa causes platelets to aggregate. The binding of fibrinogen is mediated in part by the Arg-Gly-Asp (RGD) recognition sequence which is common to the adhesive proteins that bind GPIIb/IIIa.
Several RGD-peptidomimetic compounds have been reported which block fibrinogen binding and prevent the formation of platelet thrombi.
European Patent Application Publication Number 478363 relates to compounds having the general formula: 
European Patent Application Publication Number 478328 relates to compounds having the general formula: 
European Patent Application Publication Number 525629 (corresponds to Canadian Patent Application Publication Number 2,074,685) discloses compounds having the general formula: 
PCT Patent Application 9307867 relates to compounds having the general formula: 
European Patent Application Publication Number 512831 relates to compounds having the general formula: 
Copending commonly assigned U.S. patent application (U.S. Ser. No. 08/337,920, filed Nov. 10, 1994, Wityak et al.; published as WO95/13155, Jun. 1, 1995) discloses compounds having the general formula: 
which are useful as IIB/IIIA antagonists.
Copending commonly assigned U.S. patent application (U.S. Ser. No. 08/455,768, filed May 31, 1995, Voss et al.) discloses compounds having the general formula: 
which are useful as avb3 antagonists.
None of the above references teaches or suggests the compounds of the present invention which are described in detail below.
One aspect of this invention provides novel compounds of Formula I (described below) which are useful as antagonists of the platelet glycoprotein IIb/IIIa complex. The compounds of the present invention inhibit the binding of fibrinogen to platelet glycoprotein IIb/IIIa complex and inhibit the aggregation of platelets. The present invention also includes pharmaceutical compositions containing such compounds of Formula I, and methods of using such compounds of Formula I, and methods of using such compounds for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.
The present invention also includes methods of treating cardiovascular disease, thrombosis or harmful platelet aggregation, reocclusion following thrombolysis, reperfusion injury, or restenosis by administering a compound of Formula I alone or in combination with one or more additional therapeutic agents selected from: anti-coagulants such as warfarin or heparin; anti-platelet agents such as aspirin, piroxicam or ticlopidine; thrombin inhibitors such as boroarginine derivatives, hirudin or argatroban; or thrombolytic agents such as tissue plasminogen activator, anistreplase, urokinase or streptokinase; or combinations thereof.
Also included in the present invention are pharmaceutical kits comprising one or more containers containing pharmaceutical dosage units comprising a compound of Formula I, for the treatment of cell adhesion related disorders, including but not limited to thromboembolic disorders.
This invention relates to novel compounds of Formula I 
and pharmaceutically acceptable salt or prodrug forms thereof, wherein:
B is selected from
R2(R2a)Nxe2x80x94,
R2HN(R2aNxe2x95x90)Cxe2x80x94
R2HN(R2aNxe2x95x90)CNHxe2x80x94
Z1 and Z2 are independently selected from
a single bond,
C1-C6 alkylene, optionally substituted by R2b,
C2-C6 alkenylene, optionally substituted by R2b,
C2-C6 alkynylene, optionally substituted by R2b;
wherein any carbon atom in each alkylene, alkenylene or alkynylene chain may optionally be replaced with O, S(O)0-2 or NR7, with the proviso that O, S(O)0-2 or NR7 when present are adjacent to saturated or aromatic carbon atoms;
V is selected from
a single bond,
1,4-phenylene;
wherein 1-2 carbon atoms in the phenylene may be optionally replaced with N and wherein said phenylene or azaphenylene group is optionally substituted with 1-2 R5 substituents; provided that
B, Z1, Z2 and V are chosen such that the oxime carbon in Formula I is not directly connected to an
oxygen, sulfur or nitrogen atom of B, Z1 or Z2;
L is a C1-C4 alkylene chain, C3-C4 alkenylene chain or
C3-C4 alkynylene chain optionally substituted with
C1-C4 alkyl,
C3-C7 cycloalkyl,
C4-C8 cycloalkylalkyl,
aryl,
arylmethyl,
heteroaryl,
heteroarylmethyl,
R1 is selected from
H,
C1-C6 alkyl, substituted with 0-2 R6,
C3-C7 cycloalkyl, substituted with 0-2 R6,
aryl, wherein aryl is as defined above;
R2 is selected from
H,
C1-C6 alkyl,
C3-C7 cycloalkyl,
C4-C8 cycloalkylalkyl,
arylmethyl;
R2a is selected from
H,
OH,
C1-C6 alkylcarbonyl,
arylcarbonyl,
C1-C6 alkyloxycarbonyl,
C3-C7 cycloalkyloxycarbonyl,
aryloxycarbonyl,
aryl(C1-C4 alkyl)oxycarbonyl,
C1-C6 alkylcarbonyloxy(C1-C4 alkyl)oxycarbonyl,
arylcarbonyloxy(C1-C4 alkyl)oxycarbonyl,
C3-C8 cycloalkylcarbonyloxy(C1-C4 alkyl)
oxycarbonyl;
R2b is selected from
H,
C1-C6 alkyl,
C3-C7 cycloalkyl,
C4-C8 cycloalkylalkyl,
R3 is selected from
H,
C1-C8 alkyl, substituted with 0-2 R6,
C2-C8 alkenyl, substituted with 0-2 R6,
C2-C8 alkynyl, substituted with 0-2 R6,
C3-C7 cycloalkyl, substituted with 0-2 R6,
aryl,
heteroaryl,
CONR7R8;
R4 is selected from
H,
C1-C6 alkyl,
aryl,
arylmethyl,
heteroaryl,
heteroarylmethyl,
OR14,
NR7R8,
NR11R15;
R5 is selected from
H,
halo,
CN,
C1-C4 alkyl,
C1-C4 haloalkyl,
C1-C4 alkyloxy,
C1-C4 haloalkyloxy
NR7R8;
R6 is selected from
H,
C1-C6 alkyl,
C2-C4 alkenyl,
C3-C7 cycloalkyl,
C1-C4 perfluoroalkyl,
C1-C6 alkyloxy,
C1-C6 alkylcarbonyl,
aryl,
heteroaryl,
CONR7R8 
OR14 
NR9R10,
NR11COR12,
NR11CO2R13 
NR11CONR7R8,
NR11SO2R12,
SO2R12,
SO2NR7R8, halo;
R7 and R8 are independently selected from
H,
C1-C6 alkyl,
C3-C7 cycloalkyl,
C4-C8 cycloalkylalkyl,
aryl,
aryl(C1-C4 alkyl), or, in a NR7R8 group, R7 and R8 can be taken together to form a piperidine, morpholine or thiomorpholine ring, or a piperazine ring in which N-4 is optionally substituted with C1-C4 alkyl;
R9 and R10 are independently selected from
H,
C1-C6 alkyl,
C3-C7 cycloalkyl,
C4-C8 cycloalkylalkyl,
aryl,
aryl(C1-C4 alkyl), or, in a NR9R10 group, R9 and R10 can be taken together to form a piperidine, morpholine or thiomorpholine ring, or a piperazine ring in which N-4 is optionally substituted with C1-C4 alkyl;
R11 is selected from
H,
C1-C4 alkyl,
C3-C7 cycloalkyl,
C4-C8 cycloalkylalkyl,
arylmethyl;
R12 is selected from
C1-C6 alkyl,
C3-C7 cycloalkyl,
aryl,
aryl(C1-C4 alkyl),
heteroaryl;
heteroaryl(C1-C4 alkyl);
R13 is selected from
C1-C6 alkyl,
C3-C7 cycloalkyl,
C4-C8 cycloalkylalkyl,
C1-C6 haloalkyl,
aryl(C1-C4 alkyl),
heteroaryl(C1-C4 alkyl);
R14 is selected from
H,
C1-C6 alkyl,
C1-C6 haloalkyl,
C3-C7 cycloalkyl,
C4-C8 cycloalkylalkyl,
CONR7R8,
aryl,
aryl(C1-C4 alkyl);
R15 is selected from
COR16,
CO2R17,
CONR18R19,
SO2R20,
SO2NR18R19;
R16 is selected from
H,
C1-C8 alkyl, substituted with 0-2 R6,
C2-C8 alkenyl, substituted with 0-2 R6,
C2-C8 alkynyl, substituted with 0-2 R6,
C3-C7 cycloalkyl, substituted with 0-2 R6,
aryl,
aryl(C1-C4 alkyl),
heteroaryl,
heteroaryl(C1-C4 alkyl);
R17 is selected from
C1-C8 alkyl, substituted with 0-2 R6,
C2-C8 alkenyl, substituted with 0-2 R6,
C2-C8 alkynyl, substituted with 0-2 R6,
C3-C7 cycloalkyl, substituted with 0-2 R6,
aryl(C1-C4 alkyl),
heteroaryl(C1-C4 alkyl);
R18 and R19 are independently selected from
H,
C1-C8 alkyl, substituted with 0-2 R6,
C2-C8 alkenyl, substituted with 0-2 R6,
C2-C8 alkynyl, substituted with 0-2 R6,
C3-C7 cycloalkyl, substituted with 0-2 R6,
aryl,
aryl(C1-C4 alkyl),
heteroaryl,
heteroaryl(C1-C4 alkyl); or, R18 and R19 can be taken together to form a piperidine, morpholine or thiomorpholine ring, or a piperazine ring in which N-4 is optionally substituted with C1-C4 alkyl;
R20 is selected from
C1-C8 alkyl, substituted with 0-2 R6,
C2-C8 alkenyl, substituted with 0-2 R6,
C2-C8 alkynyl, substituted with 0-2 R6,
C3-C7 cycloalkyl, substituted with 0-2 R6,
aryl,
heteroaryl,
aryl(C1-C4 alkyl),
heteroaryl(C1-C4 alkyl);
R21 and R22 are selected from
C1-C4 alkyl,
arylmethyl, or, R21 and R22 can be taken together to form a pyrrolidine, piperidine, morpholine or thiomorpholine ring, or a piperazine ring in which N-4 is optionally substituted with C1-C4 alkyl;
R23 is selected from
C1-C4 alkyl,
arylmethyl;
R24 is phenyl or naphthyl optionally substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 alkyloxy, halo, CN, C1-C4 haloalkyl, C1-C4 haloalkoxy, NO2, NH2, C1-C6 alkylamino, C2-C10 dialkylamino, C1-C6 alkylcarbonylamino, C1-C6 alkylcarbonyl, C1-C6 alkyloxycarbonyl, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, carboxy, aminocarbonyl, C1-C6 alkylaminocarbonyl, C2-C10 dialkylaminocarbonyl or methylenedioxy;
R25 is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzofuranyl, indolyl, indazolyl, benzimidazolyl or benzothiophenyl, optionally substituted with 1-3 groups selected from C1-C6 alkyl, C1-C6 alkyloxy, CN, NO2, halo, C1-C4 haloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, NH2, C1-C6 alkylcarbonylamino, C1-C6 alkylamino or C2-C10 dialkylamino;
Y is selected from
OH,
C1-C10 alkyloxy,
C3-C7 cycloalkyloxy,
C4-C8 cycloalkyloxy,
aryloxy,
arylmethyloxy,
C1-C6 alkylcarbonyloxy(C1-C4 alkyl)oxy,
C1-C6 alkyloxycarbonyloxy(C1-C4 alkyl)oxy,
C3-C7 cycloalkylcarbonyloxy(C1-C4 alkyl)oxy,
C3-C7 cycloalkyloxycarbonyloxy(C1-C4)oxy,
aryloxycarbonyloxy(C1-C4 alkyl)oxy,
arylcarbonyloxy (C1-C4 alkyl)oxy,
(C1-C4 alkyloxy(C1-C6)alkyl)carbonyloxy(C1-C4 alkyl)oxy,
(5-(C1-C6 alkyl)-1,3-dioxa-cyclopenten-2-one-4-yl)methyloxy,
(5-aryl-1,3-dioxa-cyclopenten-2-one-4-yl)methyloxy,
(R21)(R22)N(C1-C6 alkyl)oxy-,
(R21)(R22)(R23)N+(C1-C6 alkyl)oxy-(Xxe2x88x92), where Xxe2x88x92
is a pharmaceutically acceptable anionic group such as halide, sulfate, organosulfonate or organocarboxylate;
wherein aryl is a phenyl or naphthyl group optionally substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 alkyloxy, halo, CN, C1-C4 haloalkyl, C1-C4 haloalkoxy, NO2, NH2, C1-C6 alkylamino, C2-C10 dialkylamino, C1-C6 alkylcarbonylamino, C1-C6 alkylcarbonyl, C1-C6alkyloxycarbonyl, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, 1-C6 alkylsulfonylamino, carboxy, aminocarbonyl, C1-C6 alkylaminocarbonyl, C2-C10 dialkylaminocarbonyl, methylenedioxy and one substituent selected from R24CO, R24O, R24NH, R24S, R24SO, R24SO2, R24NHCO, R24CONH, R24NHSO2, R24SO2NH or phenyl optionally substituted with 1-3 substituents chosen from C1-C6 alkyl, C1-C6 alkyloxy, halo or C1-C4 haloalkyl, except that in the case for R20 aryl can be as defined above but where the three substituents on the phenyl and naphthyl groups may in addition include one substituent selected from R25, R25CO, R25O, R25NH, R25S, R25SO, R25SO2, R25NHCO, R25CONH, R25NHSO2 or R25SO2NH;
and wherein heteroaryl is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzofuranyl, indolyl, indazolyl, benzimidazolyl or benzothiophenyl, optionally substituted with 1-3 groups selected from C1-C6 alkyl, C1-C6 alkyloxy, CN, NO2, halo, C1-C4 haloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, NH2, C1-C6 alkylcarbonylamino, C1-C6 alkylamino, C2-C10 dialkylamino or one substituent selected from phenyl optionally substituted with 1-3 substituents chosen from C1-C6 alkyl, C1-C6 alkyloxy, halo or C1-C4 haloalkyl, except that in the case for R20 heteroaryl can be defined above but where the three substituents on the heteroaryl ring may in addition include one substituent selected from R24CO, R24O, R24NH, R24S, R24SO, R24SO2, R24NHCO, R24CONH, R24NHSO2, R24SO2NH, R25, R25CO, R25O, R25NH, R25S, R25SO,R25SO2, R25NHCO, R25CONH, R25NHSO2 or R25SO2NH;
Preferred compounds of the present invention are those compounds of Formula I defined above wherein:
B is selected from
R2(R2a)Nxe2x80x94,
R2HN(R2aNxe2x95x90)Cxe2x80x94,
R2HN(R2aNxe2x95x90)CNHxe2x80x94, 
Z1 and Z2 are independently selected from a single bond, C1-C6 alkylene, optionally substituted by R2b, wherein any carbon atom in the alkylene chain may optionally be replaced with O, with the proviso that O when present is adjacent to saturated or aromatic carbon atoms;
V is selected from
a single bond,
1,4-phenylene; wherein the phenylene group is optionally substituted with 1-2 R5 substituents; provided that
B, Z1, Z2 and V are chosen such that the oxime carbon in Formula I is not directly connected to an
oxygen, sulfur or nitrogen atom of B, Z1 or Z2;
L is a C1-C4 alkylene chain, optionally substituted with
C1-C4 alkyl,
C3-C7 cycloalkyl,
C4-C8 cycloalkylalkyl,
aryl,
arylmethyl;
R1 is selected from
H,
C1-C6 alkyl, substituted with 0-1 R6,
C3-C7 cycloalkyl, substituted with 0-1 R6,
aryl;
R2 is selected from
H,
C1-C6 alkyl,
arylmethyl;
R4 is selected from
H,
C1-C6 alkyl,
aryl,
arylmethyl,
OR14,
NR7R8,
NR11R15;
R5 is selected from
H,
halo,
C1-C4 alkyl,
C1-C4 haloalkyl,
C1-C4 alkyloxy;
R12 is selected from
C1-C6 alkyl,
C3-C7 cycloalkyl,
aryl,
aryl(C1-C4 alkyl),
heteroaryl;
R13 is selected from
C1-C6 alkyl,
C3-C7 cycloalkyl,
C4-C8 cycloalkylalkyl,
C1-C6 haloalkyl,
aryl(C1-C4 alkyl);
R14 is selected from
H,
C1-C6 alkyl,
C3-C7 cycloalkyl,
C4-C8 cycloalkylalkyl,
aryl,
aryl(C1-C4 alkyl);
R16 is selected from
C1-C8 alkyl, substituted with 0-2 R6,
C2-C8 alkenyl, substituted with 0-2 R6,
C2-C8 alkynyl, substituted with 0-2 R6,
C3-C7 cycloalkyl, substituted with 0-2 R6,
aryl,
aryl (C1-C4 alkyl),
heteroaryl,
heteroaryl (C1-C4 alkyl);
R21 and R22 are selected from C1-C4 alkyl, or
R21 and R22 can be taken together to form a pyrrolidine, piperidine or morpholine ring;
R23 is selected from C1-C4 alkyl;
Y is selected from
OH,
C1-C10 alkyloxy,
C3-C7 cycloalkyloxy,
C4-C8 cycloalkyloxy,
arylmethyloxy,
C1-C6 alkylcarbonyloxy(C1-C4 alkyl)oxy,
C1-C6 alkyloxycarbonyloxy(C1-C4 alkyl)oxy,
C3-C7 cycloalkylcarbonyloxy(C1-C4 alkyl)oxy,
C3-C7 cycloalkyloxycarbonyloxy(C1-C4)oxy,
aryloxycarbonyloxy(C1-C4 alkyl)oxy,
arylcarbonyloxy(C1-C4 alkyl)oxy,
(C1-C2 alkyloxy(C1-C4)alkyl)carbonyloxy(C1-C2 alkyl)oxy, (5-(C1-C4 alkyl)-1,3-dioxa-cyclopenten-2-one-4-yl)methyloxy, (5-phenyl-1,3-dioxa-cyclopenten-2-one-4-yl)methyloxy,
(R21)(R22)N(C2-C4 alkyl)oxy-,
(R21)(R22)(R23)N+(C2-C4 alkyl)oxy-(Xxe2x88x92), where Xxe2x88x92 is a pharmaceutically acceptable anionic group such as halide, sulfate, organosulfonate or organocarboxylate;
and wherein aryl and heteroaryl are defined as before;
More preferred are those preferred compounds defined above wherein:
B is selected from
R2HN(R2aNxe2x95x90)Cxe2x80x94,
R2HN(R2aNxe2x95x90)CNHxe2x80x94, 
L is a C1-C4 alkylene chain, optionally substituted with C1-C4 alkyl;
R1 is selected from
H,
C1-C6 alkyl,
C3-C7 cycloalkyl,
aryl;
R2 is selected from
H,
C1-C6 alkyl,
benzyl;
R2a is selected from
H,
OH
C1-C6 alkyloxycarbonyl,
C3-C7 cycloalkyloxycarbonyl,
benzyloxycarbonyl,
C1-C4 alkylcarbonyloxy(C1-C2 alkyl)oxycarbonyl,
C3-C8 cycloalkylcarbonyloxy(C1-C2 alkyl)oxycarbonyl;
R2b is selected from
H,
C1-C6 alkyl;
R3 is selected from
H,
C1-C8 alkyl, substituted with 0-R6,
C2-C8 alkenyl, substituted with 0-1 R6,
C2-C8 alkynyl, substituted with 0-1 R6,
C3-C7 cycloalkyl, substituted with 0-1 R6,
aryl,
heteroaryl,
CONR7R8;
R4 is selected from
H,
NR11R15;
R11 is selected from
H,
C1-C4 alkyl;
R13 is selected from
C1-C6 alkyl,
C3-C7 cycloalkyl,
C4-C8 cycloalkylalkyl,
C1-C6 haloalkyl,
arylmethyl;
R16 is selected from
C1-C8 alkyl, substituted with 0-2 R6,
aryl,
aryl(C1-C4 alkyl);
R17 is selected from
C1-C8 alkyl, substituted with 0-2 R6,
aryl(C1-C4 alkyl);
R18 and R19 are selected from
H,
C1-C8 alkyl, substituted with 0-2 R6,
aryl,
aryl(C1-C4 alkyl);
R20 is selected from
C1-C8 alkyl, substituted with 0-2 R6,
aryl,
aryl(C1-C4 alkyl),
heteroaryl,
heteroaryl(C1-C4 alkyl); and
wherein aryl and heteroaryl are as defined before.
Most preferred are those more preferred compounds defined above wherein:
B is selected from:
H2N(R2aNxe2x95x90)Cxe2x80x94,
H2N(R2aNxe2x95x90)CNHxe2x80x94,
Z1 and Z2 are a single bond;
V is selected from
1,4-phenylene,
wherein the phenylene group is optionally substituted with 1-2 R5 substituents;
L is a C1-C4 alkylene chain;
R1 is selected from
H,
C1-C6 alkyl;
R2 is H;
R2a is selected from
H,
OH
C1-C2 alkyloxycarbonyl,
C5-C7 cycloalkyloxycarbonyl,
benzyloxycarbonyl,
C1-C2 alkylcarbonyloxy(C1-C2 alkyl)oxycarbonyl,
C5-C6 cycloalkylcarbonyloxy(C1-C2 alkyl)oxycarbonyl;
R3 is selected from
H,
C1-C6 alkyl,
C2-C6 alkenyl,
C2-C6 alkynyl,
aryl,
aryl(C1-C2 alkyl),
heteroaryl,
heteroaryl(C1-C2 alkyl),
CONR7R8;
R5 is selected from
H,
halo,
methyl,
trifluoromethyl,
methoxy;
R11 is H or methyl;
R15 is selected from
CO2R17,
SO2R20;
R16 is selected from
C1-C8 alkyl, substituted with 0-1 R6,
aryl,
aryl(C1-C4 alkyl);
R17 is selected from
C1-C8 alkyl, substituted with 0-1 R6,
aryl(C1-C4 alkyl);
R18 and R19 are selected from
H,
C1-C8 alkyl, substituted with 0-1 R6,
aryl,
aryl(C1-C4 alkyl);
R20 is selected from
C1-C8 alkyl, substituted with 0-1 R6,
aryl,
aryl(C1-C4 alkyl),
heteroaryl,
heteroaryl(C1-C4 alkyl);
R21 and R22 are selected from C1-C2 alkyl, or
R21 and R22 can be taken together to form a pyrrolidine,
piperidine or morpholine ring;
R23 is selected from C1-C2 alkyl;
Y is selected from
OH,
C1-C10 alkyloxy,
benzyloxy,
C1-C4 alkylcarbonyloxy(C1-C2 alkyl)oxy,
C1-C4 alkyloxycarbonyloxy(C1-C2 alkyl)oxy,
C5-C6 cycloalkylcarbonyloxy(C1-C2 alkyl)oxy,
C5-C6 cycloalkyloxycarbonyloxy(C1-C2)oxy,
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy,
(5-methyl-1,3-dioxa-cyclopenten-2-one-4-yl)methyloxy, (5-phenyl-1,3-dioxa-cyclopenten-2-one-4-yl)methyloxy, ((R21)(R22)N)ethoxy-,
((R21)(R22)(R23)N+)ethoxy- (Xxe2x88x92), where Xxe2x88x92 is a pharmaceutically acceptable anionic group such as halide, sulfate, organosulfonate or organocarboxylate;
and wherein aryl and heteroaryl are defined as above;
Illustrative compounds of the present invention are those most preferred compounds of Formula I which are:
3-[3-[[(4-amidinophenylmethylene)amino]oxy]-1-oxopropylamino]-2-(S)-[(3-methylphenyl)sulfonylamino]propanoic acid
3-[2-[[(4-amidinophenylmethylene)amino]oxy]-1-oxoethylamino]-2-(S)-[(3-methylphenyl)sulfonylamino]propanoic acid
3-[3-[[(4-amidinophenylmethylene)amino]oxy]-1-oxopropylamino]-2-(S)-[n-butyloxycarbonylamino]propanoic acid
3-[2-[[(4-amidinophenylmethylene)amino]oxy]-1-oxoethylamino]-2-(S)-[n-butyloxycarbonylamino]propanoic acid
3-[3-[[[1-(4-amidinophenyl)ethylidene]amino]oxy]-1-oxopropylamino]-2-(S)-[(3-methylphenyl)sulfonylamino]propanoic acid
3-[2-[[[1-(4-amidinophenyl)ethylidene]amino]oxy]-1-oxoethylamino]-2-(S)-[(3-methylphenyl)sulfonylamino]propanoic acid
3-[3-[[[1-(4-amidinophenyl)ethylidene]amino]oxy]-1-oxopropylamino]-2-(S)-[n-butyloxycarbonylamino]propanoic acid
3-[2-[[[1-(4-amidinophenyl)ethylidene]amino]oxy]-1-oxoethylamino]-2-(S)-[n-butyloxycarbonylamino]propanoic acid
and nitrogen-derivatized prodrug forms of these illustrative compounds in which the prodrug moeity is chosen from
OH,
methoxycarbonyl,
ethoxycarbonyl,
cyclohexylcarbonyl,
benzyloxycarbonyl,
methylcarbonyloxymethylcarbonyl,
ethylcarbonyloxylmethylcarbonyl,
cyclohexylcarbonyloxymethylcarbonyl;
and esters of these illustrative compounds chosen from
methyl,
ethyl,
i-propyl,
n-butyl,
i-butyl,
benzyl,
methylcarbonyloxymethyl,
ethylcarbonyloxymethyl,
t-butylcarbonyloxyinethyl,
cyclohexylcarbonyloxymethyl,
cyclohexyloxycarbonyloxymethyl,
t-butyloxycarbonyloxymethyl,
dimethylaminoethyl,
diethylaminoethyl,
pyrrolidinylethyl,
morpholinylethyl,
trimethylammoniumethyl (Xxe2x88x92);
The compounds of Formula I of the present invention are useful for the treatment (including prevention) of thromboembolic disorders. The term xe2x80x9cthromboembolic disordersxe2x80x9d as used herein includes conditions involving platelet activation and aggregation, such as arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, thrombosis, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, myocardial infarction, cerebral embolism, kidney embolisms, pulmonary embolisms, or such disorders associated with diabetes, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I described above.
The compounds of the present invention are useful for inhibiting the binding of fibrinogen to blood platelets, inhibiting aggregation of blood platelets, treating thrombus formation or embolus formation, or preventing thrombus or embolus formation in a mammal.
The compounds of the invention may be used as a medicament for blocking fibrinogen from acting at its receptor site in a mammal.
Compounds of the invention may be administered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex IIb/IIIa receptor is desired. They are useful in surgery on peripheral arteries (arterial grafts, carotid endarterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption, and where the aggregated platelets may form thrombi and thromboemboli. The compounds of the present invention may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli.
Extracorporeal circulation is routinely used during cardiovascular surgery in order to oxygenate blood. Platelets adhere to surfaces of the extracorporeal circuit. Adhesion is dependent on the interaction between GPIIb/IIIa on the platelet membranes and fibrinogen adsorbed to the surface of the extracorporeal circuit. Platelets released from artificial surfaces show impaired homeostatic function. The compounds of the invention may be administered to prevent such ex vivo adhesion.
The compounds of the present invention may be used for other ex vivo applications to prevent cellular adhesion in biological samples.
Other applications of these compounds include prevention of platelet thrombosis, thromboembolism, and reocclusion during and after thrombolytic therapy and prevention of platelet thrombosis, thromboembolism and reocclusion after angioplasty of coronary and other arteries and after coronary artery bypass procedures. The compounds of the present invention may also be used to prevent myocardial infarction. The compounds of the present invention are useful as thrombolytics for the treatment of thromboembolic disorders.
The compounds of the present invention can also be administered in combination with one or more additional therapeutic agents select from: anti-coagulant or coagulation inhibitory agents, such as heparin or warfarin; anti-platelet or platelet inhibitory agents, such as aspirin, piroxicam, or ticlopidine; thrombin inhibitors such as boropeptides, hirudin or argatroban; or thrombolytic or fibrinolytic agents, such as plasminogen activators, anistreplase, urokinase, or streptokinase.
The compounds of Formula I of the present invention can be administered in combination with one or more of the foregoing additional therapeutic agents, thereby to reduce the doses of each drug required to achieve the desired therapeutic effect. Thus, the combination treatment of the present invention permits the use of lower doses of each component, with reduced adverse, toxic effects of each component. A lower dosage minimizes the potential of side effects of the compounds, thereby providing an increased margin of safety relative to the margin of safety for each component when used as a single agent. Such combination therapies may be employed to achieve synergistic or additive therapeutic effects for the treatment of thromboembolic disorders.
By xe2x80x9ctherapeutically effective amountxe2x80x9d it is meant an amount of a compound of Formula I that when administered alone or in combination with an additional therapeutic agent to a cell or mammal is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.
By xe2x80x9cadministered in combinationxe2x80x9d or xe2x80x9ccombination therapyxe2x80x9d it is meant that the compound of Formula I and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
The term anti-coagulant agents (or coagulation inhibitory agents), as used herein, denotes agents that inhibit blood coagulation. Such agents include warfarin (available as Coumadin(trademark)) and heparin.
The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA), and piroxicam. Piroxicam is commercially available from Pfizer Inc. (New York, N.Y.), as Feldane(trademark). Other suitable anti-platelet agents include ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use. Still other suitable platelet inhibitory agents include thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.
The phrase thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of the serine protease thrombin and other inhibitors of thrombin synthesis such as Factor XA. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted. Such inhibitors include boroarginine derivatives and boropeptides, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal a-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitors include compounds described in Kettner et al., U.S. Pat. No. 5,187,157 and European Patent Application Publication Number 293 881 A2, the disclosures of which are hereby incorporated herein by reference. Other suitable boroarginine derivatives and boropeptide thrombin inhibitors include those disclosed in PCT Application Publication Number 92/07869 and European Patent Application Publication Number 471 651 A2, the disclosures of which are hereby incorporated herein by reference, in their entirety.
The phrase thrombolytics (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof. Tissue plasminogen activator (tPA) is commercially available from Genentech Inc., South San Francisco, Calif. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosures of which are hereby incorporated herein by reference herein, in their entirety. Anistreplase is commercially available as Eminase(trademark). The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.
Administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.
GPIIb/IIIa is known to be overexpressed in metastatic tumor cells. The compounds or combination products of the present invention may also be useful for the treatment, including prevention, of metastatic cancer.
The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the binding of fibrinogen to platelet GPIIb/IIIa. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving GPIIb/IIIa. The compounds of the present invention may also be used in diagnostic assays involving platelet GPIIb/IIIa.
The compounds herein described may have asymmetric centers. Unless otherwise indicated, all chiral, diastereomeric and racemic forms are included in the present invention. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. It will be appreciated that compounds of the present invention that contain asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
When any variable (for example but not limited to, R1, R2, R2a, or R4, etc.) occurs more than one time in any constituent or in any formula, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 and R6 at each occurrence is selected independently from the defined list of possible R6.
When a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a bond joining a substituent to another group is not specifically shown or the atom in such other group to which the bond joins is not specifically shown, then such substituent may form a bond with any atom on such other group.
When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of Formula I, then such substituent may be bonded via any atom in such substituent. For example, when the substituent is pyridyl, or pyrozaoly, etc., unless specified otherwise, said pyridyl or pyrazoly, group may be bonded to the rest of the compound of Formula I via any atom in such pyridyl or pyrazoly, group.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term xe2x80x9csubstitutedxe2x80x9d, as used herein, means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (for example, xe2x80x9cC1-C8xe2x80x9d denotes alkyl having 1 to 8 carbon atoms); xe2x80x9calkyloxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; xe2x80x9ccycloalkylxe2x80x9d is intended to include saturated ring groups, including mono-, bi-, or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like; and xe2x80x9calkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbonxe2x80x94carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
The terms xe2x80x9calkylenexe2x80x9d, xe2x80x9calkenylenexe2x80x9d, xe2x80x9cphenylenexe2x80x9d, and the like, refer to alkyl, alkenyl, and phenyl groups, respectively, which are connected by two bonds to the rest of the structure of Formula I. Such xe2x80x9calkylenexe2x80x9d, xe2x80x9calkenylenexe2x80x9d, xe2x80x9cphenylenexe2x80x9d, and the like, may alternatively and equivalently be denoted herein as xe2x80x9c-(alkyl)-xe2x80x9d, xe2x80x9c-(alkenyl)-xe2x80x9d and xe2x80x9c-(phenyl)-xe2x80x9d, and the like.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound of Formula I is modified by making acid or base salts of the compound of Formula I. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
xe2x80x9cProdrugsxe2x80x9d are considered to be any covalently bonded carriers which release the active parent drug according to Formula I in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of Formula I are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds of Formula I wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula I, and the like. Examples of the prodrug forms of the compounds of the present invention include the following esters:
methyl; ethyl; isopropyl; methylcarbonyloxymethyl-;
ethylcarbonyloxymethyl-; t-butylcarbonyloxymethyl-;
cyclohexylcarbonyloxymethyl-;
1-(methylcarbonyloxy)ethyl-; 1-(ethylcarbonyloxy)ethyl-;
1-(t-butylcarbonyloxy)ethyl-;
i-propyloxycarbonyloxymethyl-;
cyclohexylcarbonyloxymethyl-;
t-butyloxycarbonyloxymethyl-;
1-(i-propyloxycarbonyloxy)ethyl-;
1-(cyclohexyloxycarbonyloxy)ethyl-;
1-(t-butyloxycarbonyloxy)ethyl-; dimethylaminoethyl-;
diethylaminoethyl-; (5-(5-butyl)-1,3-dioxacyclopenten-2-on-4yl)methyl-; (5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methyl-; (1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methyl-; 1-(2-(2-methyoxypropyl)-carbonyloxy)ethyl-.
The pharmaceutically acceptable salts of the compounds of Formula I include the conventional non-toxic salts or the quaternary ammonium salts of the compounds of Formula I formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, benzenesulphnic, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula I which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
The pharmaceutically acceptable salts of the acids of Formula I with an appropriate amount of a base, such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or a quaternary ammonium hydroxide such as tetramethylammoinum hydroxide and the like.
As discussed above, pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid, respectively, in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
The disclosures of all of the references cited herein are hereby incorporated herein by reference in their entirety.
The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The following abbreviations are used herein:
Scheme I describes one synthetic sequence to the compounds of this invention. In Scheme I, B is as described above or may also represent a precursor to B, such as nitrile or halogen, or a protected version of B. All other abbreviations in Scheme I are as defined above. An appropriately substituted oxime or ketoxime is generated from the appropriate aldehyde or ketone by treatment with hydroxylamine according to standard methods. Alkylation of the oxime in basic conditions, such as t-BuOK or NaH, with appropriate haloalkyl esters affords the O-alkylated oximino derivatives. The ester is then saponified or hydrolyzed to the carboxylic acid using conventional methods known to one skilled in the art of organic synthesis. Intermediates containing alkali-sensitive functionality, such as nitrile, may be deesterified with excellent chemoselectivity using sodium trimethylsilanolate according to the procedure of Laganis and Ehenard (Tetrahedron Lett. 1984, 25, 5831). Coupling of the resulting acids to an appropriately substituted b-amino ester using standard coupling reagents, such as DCC/HOBt or TBTU, affords the desired amide. If B is protected with, for example, Cbz or Boc; it may now be deprotected using methods known to one skilled in the art of organic synthesis. This is followed by conversion of the ester to the carboxylic acid using, for example, LiOH/THF/H2O or other standard methods. If B is a precursor such as nitrile, as in Scheme Ia, the nitrile is then converted to the amidine via the imidate or thioimidate under standard conditions to give the prodrug esters. This is followed by ester saponification (e.g., LiOH/THF/H2O), hydrolysis or enzymolysis to give the acids. 
An exemplification of the method described in Scheme I is shown in Scheme II. 4-Cyanophenyloxime is treated with t-BuOK in THF and tert-butyl bromoacetate. The resulting tert-butyl 4-cyanophenyloximino-O-alkanoate is hydrolyzed to the acid by treatment with TFA in methylene chloride. The resulting acid is then coupled to an appropriately substituted ester of a beta-amino acid using, for example, TBTU and triethylamine in DMF. The nitrile may then be converted to the amidine by first treating with anhydrous HCl in dry methanol to afford the imidate, followed by treatment of the imidate with ammonium carbonate in dry methanol. The ester may then be saponified using LiOH in methanol/water. 
A related method of preparation for compounds of the present invention involves conversion of the 4-cyanophenyloximino-O-alkanoate ester intermediate shown in Scheme II to the corresponding amidine using a Pinner sequence. Protection of the amidine as the Boc-derivative and saponification of the ester group provides the corresponding Boc-amidinophenyoximino-O-alkanoic acid. Coupling with b-amino acid esters and acidic Boc-removal provides the desired oximino-O-alkanoyl-b-aminoalaninyl esters. Saponification as described above gives the free acids.
Oximes of the present invention are prepared from appropriate aldehydes or ketones; these may in turn be prepared by oxidation of the corresponding alcohols. Oximes suitable for use in this invention are described by Wityak et al. (J. Med. Chem. 1997, 40, 50-60) and Xue et al. (J. Med. Chem. 1997, 40, 2064-2084). Alkylation of the oximes may be carried out by treatment of the oxime with a suitable base and an alkylating agent having a suitable leaving group, or by addition of the oxime across a double bond. The alkylating agent may have an ester functionality which may be manipulated as shown in Schemes I and II, or it may already be coupled to an appropriately substituted b-amino acid.
The appropriately substituted racemic b-amino acids may be purchased commercially or, as is shown in Scheme III, Method 1, prepared from the appropriate aldehyde, malonic acid and ammonium acetate according to the procedure of Johnson and Livak (J. Am. Chem. Soc. 1936, 58, 299). Racemic b-substituted-b-amino esters may be prepared through the reaction of dialkylcuprates or alkyllithiums with 4-benzoyloxy-2-azetidinone followed by treatment with anhydrous acid in ethanol (Scheme III, Method 2) or by reductive amination of b-keto esters as is described in WO9316038. (Also see Rico et al., J. Org. Chem. 1993, 58, 7948-51.) Enantiomerically pure b-substituted-b-amino acids can be obtained through the optical resolution of the racemic mixture or can be prepared using numerous methods, including: Arndt-Eistert homologation of the corresponding a-amino acids as shown in Scheme III, Method 3 (see Meier, and Zeller, Angew, Chem. Int. Ed. Engl. 1975, 14, 32; Rodriguez, et al. Tetrahedron Lett. 1990, 31, 5153; Greenlee, J. Med. Chem. 1985, 28, 434 and references cited within); and through an enantioselective hydrogenation of a dehydroamino acid as is shown in Scheme III, Method 4 (see Asymmetric Synthesis, Vol. 5, (Morrison, ed.) Academic Press, New York, 1985). A comprehensive discussion of the preparation of b-amino acid derivatives may be found in patent application WO 9307867, the disclosure of which is hereby incorporated by reference. 
The synthesis of N2-substituted diaminopropionic acid derivatives can be carried out via Hoffman rearrangement of a wide variety of asparagine derivatives as described in Synthesis, 266-267, (1981), or from commercially available Z-protected diaminopropionate as described by Xue et al. (J. Med. Chem. 1997, 40, 2064-2084; Bioorg. Med. Chem. Lett. 1996, 6, 339-344; and references cited therein). Xue et al. (J. Med. Chem. 1997, 40, 2064-2084, and references cited therein) describe a variety of methods which may be used for the preparation of b-amino acids suitable for the synthesis of compounds of the present invention.